Hot-melt extrusion (HME) is a widely applied technique in the plastics industry and has been demonstrated to be a viable method to prepare several dosage forms of pharmaceutical compositions. Hot-melt extruded dosage forms are typically mixtures of active medicaments, functional excipients, and processing aids. HME also offers several functional advantages over traditional pharmaceutical processing techniques such as wet, dry and melt granulation. Such advantages include absence of solvents, few processing steps, continuous operation, the possibility of the formation of solid dispersions/solid solutions and improved bioavailability. HME process can be carried out in a single screw extruder or a twin-screw extruder. Due to the self-cleaning advantage and configurable mixing capability of the co-rotating twin-screw extruder, the co-rotating twin-screw is increasingly preferred as the device for carrying out the HME process. Conventional HME process involves embedding a drug in a carrier under controlled conditions such as temperature, residence time, mixing energy input, feed rate and pressure and forcing it through an orificed die or an open die to collect the hot viscous mass or melt in the form of a strand, film or a lump. A conventional extruder for HME process includes an intake zone through which the mixture of active ingredients and suitable excipients are introduced, a melt zone for forming a viscous mass or melt and a conveying zone for conveying the hot viscous mass or melt out of the extruder. The barrel in the extruder is divided into different temperature zones that are set to specific temperatures as per the need of the extrusion process. Typically, the temperature of the viscous mass/melt along the length of the barrel is maintained such that there is no solidification inside the extruder. (For example, Vasanthavada et al., 2010 suggest the cooler zone is towards the feeder and the warmer zone towards the exit). Heat for fusion is supplied by the mechanical shear dissipation from the rotating screws inside the extruder as well as from the outside heaters that are typically electrical in nature. The extrudate exiting the extruder is a hot viscous mass or melt that can be shaped to a desired form depending on the shape of the die (cylindrical die yields a strand or slit die yields a film) that can be sized to desired lengths or passed on to a chill roll unit and pressed against the rollers to form thin sheet that will generally flake into smaller pieces.
The extrudate is then subjected to further processing by auxiliary downstream devices, typically a size reduction step to form particles of required size. Free flowing particles are used for compression, capsule filling and/or molding into tablets. Fine particles with narrow size distribution are generally required for oral suspensions. There are limitations on the materials that can be used as carriers; as such materials should be amenable to size reduction since low melting solids cannot be milled effectively and efficiently. The limitation in selection of material that can be size reduced may be a factor in restricting the enhancement in solubility, bioavailability, tastemasking, or sustained release of the pharmaceutical composition.
Spray congealing and spray drying are also known methods for producing fine particles. Spray congealing is carried out by spraying a viscous melt to generate droplets in a cooling chamber. Spray drying is carried out with a fluid material containing solvents that is injected into a heated chamber where the generated droplets are dried to form fine powders. Both processes require large foot-prints for limited capacities of production. Spray congealing is a dedicated facility for limited type of fluid material and offers limited flexibility for varied pharmaceutical preparations. Spray drying involves use of a large amount of solvents that may not meet environmental concerns and does not offer scalability from laboratory equipment to commercial equipment. All batch type processes create variability from lot to lot.
Conventional HME process further requires a multiple equipment setup, under controlled environmental conditions to process pharmaceutical compositions. The process also tends to compromise on one or more desired properties of the pharmaceutical composition.
U.S. Pat. No. 6,318,650 to Breitenbach describes a process for the continuous production of solid, particulate preparations of bioactive substances, in which the bioactive substances are homogeneously dispersed in a matrix of thermoplastic auxiliaries, in a screw extruder having an extruder barrel. The extruder is divided into a plurality of zones, so that the process comprises firstly melting the matrix auxiliaries and mixing the bioactive components with the matrix auxiliaries in a heatable zone of the extruder to form a mixture, and subsequently cooling, precomminuting and finally grinding the mixture in a cooling zone of the extruder to form a powder. It is crucial for success of the process that pure conveying elements are employed in the first part of the cooling zone, in order to minimize the energy input and reduce the shear stress and to maximize the rate of cooling of the melt below the softening point. The process further requires that the matrix polymers are preferably soluble in water but are at least swellable in water. Accordingly, this process is not suitable for all excipients such as fatty acids, glyceryl behenate and waxes; and particularly stearic acid that form a waxy lump on cooling that is not amenable for comminuting inside the extruder. The pure conveying zone resulting in rapid cooling prior to comminuting also produces some powders with exposed active medicament.
It is therefore desirable to have an improved process for the manufacture of pharmaceutical compositions in the form of particles that can enable improved drug delivery systems, using all excipients and particularly excipients such as fatty acids like stearic acid, glyceryl behenate and waxes that are not amenable to milling.